Process and intermediates for the preparation of thienopyrrole derivatives

ABSTRACT

Novel Process and Intermediates. A process for preparing a compound of formula (I) where R 4  and R 5  are as defined in the specification; and R 6  is hydrogen or a protecting group, which process comprises cyclisation of a compound of formula (II) where R 4  and R 5  and R 6  are as defined in relation to formula (I), and R 7  is nitrogen protecting group, and removing the group R 7 , and thereafter if desired, removing any protecting group R 6 . Novel intermediates and the use of these in the formation of pharmaceutical compounds is also described and claimed

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application PCT/GB2003/004211, filed Sep. 29, 2003, whichclaims priority from United Kingdom Patent Applications No. 0222909.4,filed Oct. 3, 2002, the specifications of each of which are incorporatedby reference herein. International Application PCT/GB2003/004211 waspublished under PCT Article 21(2) in English.

The present invention relates to a novel process for preparingintermediates for therapeutically effective compounds, together withnovel intermediates for use in the process.

Compounds with glycogen phosphorylase activity are described in WO02/20530. These compounds have a general formula which may berepresented as formula (A)

where X, Y and Z is selected from inter alia —S—CR⁴═CR⁵—, R⁴ and R⁵ areindependently selected from hydrogen, halo, nitro, cyano, hydroxy,fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,N-(C₁₋₆alkyl)sulphalnoyl, N,N,-(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino and C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino;

-   n is 0-4, and R¹, R² and R³ are various specified organic groups.

These compounds are generally prepared by a reacting an acid of formula(B)

with an appropriate amine. Acids of formula (B) are prepared accordingto the following scheme:

However, this process is difficult to effect as it may proceedexplosively.

The applicants have found an improved process for the production ofcertain intermediates.

The present invention provides a process for preparing a compound offormula (I)

where R⁴ and R⁵ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆-alkanoylamino, N-(C-₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,C₁₋₆-alkylS(O)_(a) wherein a is 0 to 2, C-₁₋₆alkoxycarbonyl,C₁₋₆-alkoxycarbonylamino, N-(C₁₋₆alkyl)sulphamoyl,N,N,-(C-₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC-₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino; and R⁶ is hydrogen or aprotecting group,which process comprises cyclisation of a compound of formula (II)

where R⁴, R⁵ and R⁶ are as defined in relation to formula (I), and R⁷ isa nitrogen-protecting group, and removing the group R⁷, and thereafterif desired, removing any protecting group R⁶.

Cyclisation is suitably effected in an organic solvent such asdimethylformamide (DMF), N-methylpyrrolidone or dimethylacetamide, inthe presence of a base, preferably a weak base such as an alkali metalcarbonate or bicarbonate, such as potassium carbonate. The reaction issuitably carried out at elevated temperatures, for example of from 40 to100° C., and preferably at about 60° C. Under these conditions, R⁷ isgenerally removed in the same reaction step. Depending upon the natureof the group employed however, it might be necessary to remove R⁷ in asubsequent step, for example by acid or base hydrolysis reactions.

Acid hydrolysis reactions may be carried out using conventional methods,and in particular using acids such as trifluoromethanesulphonic acid,acetic acid or hydrochloric acid. Base hydrolysis reactions are suitablyeffected in the presence of bases, such as alkali metal hydrides orhydroxides, and in particular sodium or potassium hydroxide.

Suitable example of protecting groups R⁷ are listed in T.W. Green,Protecting Groups in Organic Synthesis, J. Wiley and Sons, 1991 and inparticular are those designated as nitrogen protection groups.

Particular examples of protecting groups R⁷ are groups of sub-formula(i)

where R⁸ is a hydrocarbyl or heterocyclic group, either of which may beoptionally substituted.

As used herein, the expression “hydrocarbyl” includes any structurecomprising carbon and hydrogen atoms. For example, these may be alkyl,alkenyl, alkynyl, aryl such as phenyl or napthyl, arylalkyl such asbenzyl, or cycloalkyl, cycloalkenyl or cycloalkynyl. Suitablyhydrocarbyl groups contain up to 20 and preferably up to 10 carbonatoms.

The term “aryl” refers to aromatic rings such as phenyl or naphthyl.

The term “heterocyclic” includes aromatic or non-aromatic rings, forexample containing from 4 to 20, suitably from 5 to 8 ring atoms, atleast one of which, and suitably from 1 to 4 of which is a heteroatomsuch as oxygen, sulphur or nitrogen. They may be monocyclic or havefused rings, such a bicyclic or tricyclic ring systems. Examples of suchgroups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl,triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, piperidinyl,pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl,benzothienyl or benzofuryl.

The term “heteroaryl” refers to heterocyclic groups which are aromaticin nature. Thus these may comprises cyclic aromatic hydrocarbons inwhich one or more carbon atoins have been replaced with a heteroatom. Ifthe heteroaryl group contains more than one heteroatom, the heteroatomsmay be the same or different. Examples of heteroaryl groups includepyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl,indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quniolizinyl,isoquinolyl, quinolyl phthalazinyl, naphthyridinyl, quinoxalinyl,isothiazolyl and benzo[b]thienyl. Preferred heteroaryl groups are fiveor six membered rings and contain from one to three heteroatoms.

Suitable optional substituents for heterocyclic and hydrocarbyl groupsR⁸ include nitro, cyano, halo, oxo, ═CR¹³R¹⁴, C(O)_(x)R¹², OR¹²,S(O)_(y)R¹², NR¹³R¹⁴, C(O)NR¹³R¹⁴, OC(O)NR¹³R¹⁴, ═NOR¹²,—NR¹²C(O)_(x)R¹³, —NR¹²CONR¹³R¹⁴, —N═CR¹³R¹⁴, S(O)_(y)NR¹³R¹⁴ or—NR¹²S(O)_(y)R¹³ where R¹², R¹³ and R¹⁴ are independently selected fromhydrogen or optionally substituted hydrocarbyl, or R¹³ and R¹⁴ togetherform an optionally substituted ring which optionally contains furtherheteroatoms such as S(O)_(y) oxygen and nitrogen, x is an integer of 1or 2, y is 0 or an integer of 1-3. Hydrocarbyl groups R⁸ may alsoinclude heterocyclic substituents, which may themselves be optionallysubstituted by one or more of the optional substituents listed above.Heterocyclic groups may also be substituted with hydrocarbyl groupswhich may also be optionally substituted by any of the groups listedabove.

Preferably R⁸ is a hydrocarbyl group such as alkyl, aryl or arylalkyl.Most preferably R⁸ is a straight chain alkyl group of from 1 to 6 carbonatoms, and particularly is a straight chain C₁₋₄alkyl group, such asmethyl.

Examples of protecting groups R⁷ are groups of sub-formula (i)

where R⁸ is a straight chain alkyl group of from 1 to 6 carbon atoms,and particularly is a straight chain C₁₋₄alkyl group, such as methyl.

Particular examples of ester protecting groups R⁶ are any organic groupswhich can be removed by hydrogenation or hydrolysis. These includeoptionally substituted hydrocarbyl or optionally substitutedheterocyclic groups. Such groups may be similar to those listed above inrelation to R⁷.

Suitable example of protecting groups R⁶ are also listed in T.W. Green,Protecting Groups in Organic Synthesis, J. Wiley and Sons, 1991 and inparticular are those designated as acid protecting groups.

In particular R⁶ is a hydrocarbyl group such as C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl such as phenyl, or arylalkyl such as benzyl.

Conversion of a protecting group R⁶ to hydrogen is suitably effectedusing conventional methods, for example as described in WO 02/20530. Inparticular, the compound is reacted with a base such as lithiumhydroxide, in an organic solvent such as methanol, at temperatures offrom 20-80° C., and conveniently at the reflux temperature of thesolvent.

Particular examples of groups R⁴ and R⁵ are hydrogen, halo, nitro,cyano, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy,carboxy, carbamoyl, sulphamoyl, ureido, C₁₋₆-alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆-alkoxy, C₁₋₆alkanoyl and C₁₋₆alkanoyloxy.

Suitably R⁴ and R⁵ are independently selected from hydrogen, halo,nitro, cyano, fluoromethyl, difluoromethyl, trifluoromethyl,trifluoromethoxy, carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy.

Preferably R⁴ and R⁵ are independently selected from hydrogen and halosuch as chloro, fluoro and bromo, and in particular chloro.

Most preferably R⁴ and R⁵ are halo such as chloro.

Compounds of formula (II) are suitably prepared by reacting a compoundof formula (III)

where R⁴, R⁵ and R⁶ are as defined in relation to formula (I), and R¹²is a directing nitrogen-protecting group, with a compound of formula(IV)(R⁷)₂O  (IV)where R⁷ is as defined above, under acidic condition, for example in asolvent comprising an organic acid, such as acetic acid. Elevatedtemperatures for example of from 80-150° C. and preferably from 110-130°C. are employed.

Directing nitrogen protecting groups are groups which may act asnitrogen protecting groups, but are sufficiently bulky in nature toprevent any substitution on the nitrogen atom, or the ring atom to whichit is attached. Reactions, for example deprotonation by an organolithiumreagent, are thereby directed to the adjacent position on the ring. Thusparticular examples of nitrogen directing groups R¹² are groups ofsub-formula (ii)

where R¹⁴ is a branched C₄₋₁₀alkyl group such as tertiary butyl, or anaryl or C₁₋₄alkylaryl group such as benzyl.

Compounds of formula (III) are suitably prepared by reacting a compoundof formula (V)

where R⁴ and R⁵ are as defined above in relation to formula (I) and R¹²is as defined in relation to formula (III), with a compound of formula(VI)LCH₂COOR⁶  (VI)where L is a leaving group such as halogen and in particular bromine.The reaction is suitably effected in the presence of a base such as analkali metal carbonate, bicarbonate, hydroxide or alkoxide, for instancepotassium bicarbonate in an organic solvent such as dimethylformamide.The reaction may be conducted at elevated temperatures, for example offrom 40 to 100° C., preferably from 50 to 70° C. and most preferably atabout 60° C.

Compounds of formula (V) are suitably prepared by a directed orthometallation reaction (J. Org. Chem. 20001, 66, 3662-3670). In this case,the compound of formula (V) is prepared by reacting a compound offormula (VII)

where R⁴ and R⁵ are as defined in relation to formula (I) and R¹² is asdefined in relation to formula (III), with a lithiating agent, such asN-butyl lithium, and subsequently with a formylating agent, such as acompound of formula (VIII)

where R⁹ and R¹⁰ are alkyl groups and in particular lower alkyl groupsof 1 to 4 carbon atoms, such as methyl. Reaction with the lithiatingagent is suitably effected in an organic solvent such as tetrahydrofuran(THF), at low temperatures for example of from −100° to 0° C. andpreferably from −80° to −10° C. The subsequent addition of theformylating agent is suitably also effected at low temperatures, but inthis case, temperatures of from −20° to 0° C. are adequate.

Compounds of formula (VII) are suitably prepared by subjecting acompound of formula (IX)

where R⁴ and R⁵ are as defined above in relation to formula (I), to aCurtius rearrangement reaction, in the presence of an alcohol of formulaR¹⁴OH where R¹⁴ is as defined in relation to formula (ii). In thisreaction, the compound of formula (IX) is reacted withdiphenylphosphorylazide of formula (X)

to convert the acid group to a carbonyl azide, which is thermallydecomposed to the desired amide via an isocyanate. Suitable reactionconditions are illustrated hereinafter. The reaction is suitablyeffected in the presence of a base such as triethylamine.

Compounds of formula (IX) are suitably prepared by oxidation of acompound of formula (XI)

where R⁴ and R⁵ are as defined in relation to formula (I) for exampleusing an oxidising agent such as potassium permanganate in the presenceof a base such as an alkali metal hydroxide such as sodium hydroxide.The reaction is suitably effected in an aqueous solvent at moderatetemperatures for example of from 10 to 80° C. and preferably at about40° C.

Compounds of formula (XI) where R⁴ and R⁵ are halogen can be prepared byhalogenation of compounds of formula (XII)

Suitably this is effected using a halogenating agent such as chlorineand aluminium trichloride, in an organic solvent such asdichloromethane.

Compounds of formula (II), (III), (V) and (VII) are novel and formfurther aspects of the invention.

Compounds of formula (IV), (VI), (VIII), (IX), (X), (XI) and (XII) areknown compounds or they can be prepared from known compounds byconventional methods.

Compounds of formula (I) are suitably used in the production ofpharmaceutical compounds and in particular, compounds with glycogenphosphorylase activity as described in WO 02/20530 and EP-A-1088824.

Thus in a further aspect, the invention provides a method as describedabove, for the production of a compound of formula (I) where R⁶ ishydrogen, and further comprising reacting the compound of formula (I)obtained with an amine of formula (XIII),

where R¹⁴ is selected from hydrogen and C₁₋₈alkyl,

-   m is an integer of from 0 to 4,-   each R¹⁵ is the same or different and is selected from hydrogen,    halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,    sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,    N,N-(C₁₋₆alkyl)₂amino, C₁₋₆-alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,    N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,    C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,    N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino,    C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl,    heterocyclic group and (heterocyclic group)C₁₋₆-alkyl; wherein R¹⁵    may be optionally substituted on carbon by one or more groups    selected from P and wherein if said heterocyclic group contains an    —NH— moiety that nitrogen may be optionally substituted by a group    selected from R;

each R¹⁶ is the same or different and is selected from hydrogen andC₁₋₆alkyl;

R¹⁷ is selected from hydrogen, halo, nitro, cyano, hydroxy,fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆-alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbarnoyl, N,N-(C₁₋₄alkyl)₂carbamoyl,N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0to 2, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl, sulphamoylamino,N-(C₁₋₆alkyl)sulphamoylamino, N,N-(C₁₋₆alkyl)₂sulphamoylamino,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonylaminocarbonyl,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino and a group -E-F-G-H;

wherein E and G are independently selected from a direct bond, —O—, —S—,—SO—, —SO₂—, —OC(O)—, —C(O)O—, —C(O)—, NR^(a)—, —NR^(a)C(O)—,—C(O)NR^(a)—, —SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)C(O)NR^(b)—,OC(O)NR^(a)—, —NR^(a)C(O)O—, —NR^(a)SO₂NR^(b)—, —SO₂NR^(a)C(O)— and—C(O)NR^(a)SO₂—; wherein R^(a) and R^(b) are independently selected fromhydrogen or C₁₋₆alkyl which is optionally substituted by a group V;

F is C₁₋₆alkylene optionally substituted by one or more Q or a directbond;

H is selected from aryl, C₃₋₈cycloalkyl and heterocyclic group; whereinH may be optionally substituted on carbon by one or more groups selectedfrom S and wherein if said heterocyclic group contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from T;

P, S and Q are independently selected from halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆-alkyl)₂carbamoyl, N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆-alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, N-(C₁₋₆-alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino, C₃₋₈cycloalkyl, aryl andheterocyclic group; wherein P, S and Q may be optionally andindependently substituted on carbon by one or more groups selected fromV and wherein if said heterocyclic group contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from U;

V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl,N-benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl;

R, T and U are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)carbamoyl, phenyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl wherein R, T and U may beoptionally and independently substituted on carbon by one or more groupsselected from V;

-   to produce a compound of formula (XIV)

where R⁴, R⁵, R¹⁵, R¹⁶, R¹⁷ and m are as defined above, or apharmaceutically acceptable salt or an in viva hydrolysable esterthereof.

Particular examples of compounds of formula (XIV) are compounds whereR¹⁴ is hydrogen, as described in WO 02/20530. For instance, suitablecompounds of formula (XIV) are compounds where R⁴ and R⁵ are as definedabove, R¹⁴ is hydrogen, m is 0 and R¹⁷ is a group -E-F-G-H;

wherein E, P and G are each a direct bond;

H is a C₃₋₁₂cycloalkyl which is optionally fused to a benz ring whereinH may be optionally substituted on carbon by one or more groups S whichare independently selected from halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆-alkyl)₂amino, C₁₋₆-alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆-alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆-alkylsulphonyl-N-(C₁₋₆alkyl)amino, C₃₋₈cycloalkyl, aryl andheterocyclic groups; wherein S may be optionally substituted on carbonby one or more groups selected from V;

V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl;N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl,N-benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl;

or a pharmaceutically acceptable salt thereof.

Other suitable compounds of formula (XIV) are compounds where R⁴ and R⁵are as defined above, R¹⁴ is hydrogen, m is 0, and R¹⁷ is a group-E-F-G-H;

wherein E, F and G are each a direct bond; and

H is a cyclic amide of formula

in which the point of attachment is the carbon atom adjacent to thecarbonyl group, k is 0, 1 or 2 and 1 is 0, 1 or 2 such that the sum of(k+1) is 1, 2 or 3 and wherein one of the carbon atoms governed by k orl may be replaced by sulphur and wherein H is optionally substituted onthe carbon atom adjacent to the aromatic ring by a group selected from Sand may be independently optionally substituted on nitrogen by a groupselected from T;

S is selected from halo, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl, C₁₋₆-alkylS(O)_(a) wherein a is 0to 2, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino,C₃₋₈cycloalkyl, aryl and heterocyclic group; wherein S may be optionallyand independently substituted on carbon by one or more groups selectedfrom V and wherein if said heterocyclic group contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from U;

T and U are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)carbamoyl, phenyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl wherein R, T and U may beoptionally and independently substituted on carbon by one or more groupsselected from V;

V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl,N-benzylcarbamoyl and 4-hydroxypiperidinocarbonyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof.

Yet further examples of compounds of formula (XIV) are compounds whereR¹⁴ is hydrogen, and wherein R⁴ and R⁵ are independently selected fromhydrogen, halo or C₁₋₆alkyl.

-   m is 1; R¹⁵ is hydrogen or arylC₁₋₆alkyl, R¹⁶ is hydrogen or    C₁₋₆alkyl, and R¹⁷ is selected from a group -E-F-G-H; wherein E, F    and G are each a direct bond;

H is an unsaturated five membered heterocyclic group containing at leastone nitrogen atom and one or two ring atoms selected from oxygen andsulphur and wherein H may be optionally substituted on carbon by one ormore groups S which are independently selected from halo, nitro, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino, C₃₋₈cycloalkyl and aryl groups;

or a pharmaceutically acceptable salt thereof.

Other particular examples include compounds of formula (XIV) where R¹⁴is hydrogen, R⁴ and R⁵ are independently selected from hydrogen, halo orC₁₋₆alkyl.

m is 0; and R¹⁷ is a group -E-F-G-H;

wherein E is a direct bond;

F is methylene;

wherein G is —C(O)NR^(a)—, wherein R^(a) is selected from hydrogen orC₁₋₆alkyl which is optionally substituted by a group V;

H is aryl which may be optionally substituted on carbon by one or moregroups selected from S;

S is selected from halo, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆-alkoxy, C₁₋₆alkanoyl,C₁₋₆-alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0to 2, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino,C₃₋₈cycloalkyl, aryl and heterocyclic group; wherein S may be optionallyand independently substituted on carbon by one or more groups selectedfrom V;

-   V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,    trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,    ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,    acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,    N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,    N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,    ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,    ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,    N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,    N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl,    N-benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl;    or a pharmaceutically acceptable salt thereof.

Other particular compounds of formula (XIV) are compounds where thegroup

is a group of sub-formula (ii)

where R¹⁴ is as defined above, R¹⁸ is aryl, substituted aryl,heteroaryl, or substituted heteroaryl, R¹⁹ is a bond or a group—CH(OH)—, and R²⁰ is a group —C(═O)-A or a group —CH(OH)—C(═O)-A inwhich A is NR^(d)R^(d), —NR^(a)CH₂CH₂OR^(a), or

-   each R^(a) and R^(b) is independently hydrogen or —C₁-C₈alkyl;-   each R^(d) is independently hydrogen, C₁-C₈alkyl, C₁-C₈alkoxy, aryl,    substituted aryl, heteroaryl, or substituted heteroaryl;-   each R^(c) is independently hydrogen, —C(═O)OR^(a), —OR^(a),    —SR^(a), or —NR^(a)R^(a); and each n is independently 1-3, and-   X¹ is NR^(a), —CH₂—, O or S.

Examples of substituents for aryl and heteroaryl groups Q and R^(d)include halogen, C₁₋₈alkoxy, C₁₋₈alkyl, trifluoromethyl, amino, mono ordi-(C₁₋₈alkyl)amino, nitro, cyano, carboxy or C₁₋₈alkyl esters thereof.

The invention will now be particularly described by way of example, inwhich, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations    were carried out at room or ambient temperature, that is, at a    temperature in the range of 18-25° C. and under an atmosphere of an    inert gas such as argon;-   (ii) organic solutions were dried over anhydrous magnesium sulphate;    evaporation of solvent was carried out using a rotary evaporator    under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath    temperature of up to 60° C.;-   (iii) chromatography means flash chromatography on silica gel; thin    layer chromatography (TLC) was carried out on silica gel plates;-   (iv) in general, the course of reactions was followed by TLC and    reaction times are given for illustration only;-   (v) yields are given for illustration only and are not necessarily    those which can be obtained by diligent process development;    preparations were repeated if more material was required;-   (vi) where given, NMR data is in the form of delta values for major    diagnostic protons, given in parts per million (ppm) relative to    tetramethylsilane (TMS) as an internal standard, determined at 300    MHz using perdeuterio dimethyl sulphoxide (DMSO-d₆) as solvent or    other solvents (where indicated in the text) including deuterated    chloroform CDCl₃;-   (vii) chemical symbols have their usual meanings; SI units and    symbols are used;-   (viii) reduced pressures are given as absolute pressures in Pascals    (Pa); elevated pressures are given as gauge pressures in bars;-   (ix) solvent ratios are given in volume: volume (v/v) terms;-   (x) mass spectra (MS) were run with an electron energy of 70    electron volts in the chemical ionisation (CI) mode using a direct    exposure probe; where indicated ionisation was effected by electron    impact (EI), fast atom bombardment (FAB) or electrospray (ESP);    values for m/z are given; generally, only ions which indicate the    parent mass are reported and unless otherwise stated the value    quoted is M-H)⁻;

The following abbreviations are used:

-   DMSO=dimethylsulfoxide-   DCM=dichloromethane-   THF is tetrahydrofuran-   HPLC is high performance liquid chromatography-   DMF is dimethylformamide-   THF is tetrahydrofuran

EXAMPLE 1

Thiophene-3-carbaldehyde (11.2 g, 0.1M) was dissolved in dichloromethane(400 ml) and cooled to 5° C. Aluminium chloride (33.25 g, 0.25M) wasthen added in portions so that the temperature did not rise above 10° C.After the addition was complete the temperature was allowed to rise to15° C. and chlorine gas slowly bubbled into the reaction mixture. Thetemperature was maintained between 15 and 20° C. with ice/water coolingand the reaction followed by HPLC until the mixture contained >70% of4,5-dichlorothiophene-3-carbaldehyde.

The reaction mixture was poured into ice water (1000 ml) and the organiclayer separated. The aqueous was extracted with further portions ofdichloromethane (3×200 ml) and the combined extracts washed withsaturated sodium bicarbonate, water and brine, dried over magnesiumsulphate and evaporated to give a dark oil, which crystallised onstanding. Purification by recrystallisation from hexane gave4,5-dichlorothiophene-3-carbaldehyde as light brown needles (14 g, 78%).¹H NMR (300 MHz, d⁶-DMSO) 9.9 (s, 1H), 8.0 (s, 1H)

NaOH (0.47 g) was dissolved in H₂O (8 ml) and4,5-dichlorothiophene-3-carbaldehyde from step 1 (1.42 g) added in oneportion giving a suspension. KMnO₄ (1.24 g) was added portionwise overapproximately 25 minutes whilst heating the reaction suspension in awater bath at 40° C. After complete addition the water bath temperaturewas raised to 50° C. for a further 15 minutes stirring.

Without cooling the brown precipitate was filtered off (nylon filter)and washed with H₂O. The resultant pale yellow clear solution wasacidified with concentrated aqueous hydrochloric acid to give a thickwhite suspension. The white solid was filtered off and washed with H₂O.The solid was dissolved in a mixture of ethyl acetate anddichloromethane, dried over MgSO₄, filtered and evaporated under reducedpressure to leave the desired product,4,5-dichlorothiophene-3-carboxylic acid as a white solid (1.34 g).Further product was extracted from the aqueous mother liquors usingdichloromethane. After drying over Na₂SO₄, filtration and evaporationunder reduced pressure, an additional 0.19 g of the desired4,5-dichlorothiophene-3-carboxylic acid was obtained as a white solid.¹H NMR (300 MHz, d⁶-DMSO) 13.23 (br s, 1H), 8.33 (s, 1H); ESP⁻ 195.12

Under argon 4,5-dichlorothiophene-3-carboxylic acid (10.91 g) wasdissolved in warm dry tertiary butanol (60 ml) and triethylamine (7.76ml) added followed by diphenylphosphoryl azide (DPPA) (11.99 ml). Themixture was then heated slowly to reflux and refluxed for about 12hours. On cooling the reaction mixture was poured into H₂O (˜300 ml).The resultant dark suspension was filtered, and the solid was washedwith H₂O then dried under suction to a brown powder. This was dissolvedin diethyl ether and the solution dried over MgSO₄, filtered andevaporated. Chromatography on silica gel (eluent gradient—isohexane toCH₂Cl₂) gave tert-butyl (4,5-dichloro-3-thienyl)carbamate as a paleyellow solid. Yield 12.05 g (78%). ¹H NMR (300 MHz, CDCl₃) 7.30 (br s,1H), 6.72 (br s, 1H), 1.51 (s, 9H)

The product from step 3 (445 mg) was dissolved in tetrahydrofuran (THF)under an argon atmosphere, and cooled in a dry ice/acetone bath. n-Butyllithium (1.6M in hexane) (2.5 ml) was added dropwise and the mixtureleft at this temperature for 35 minutes then allowed to warm to −10° C.(external bath temperature) over ˜15 minutes. Dimethylformamide (0.25ml) was then added dropwise and the temperature held at 10° C. for 30minutes, before being allowed to warm to room temperature. It was keptat this temperature with stirring overnight.

Saturated aqueous sodium chloride solution was then added, and themixture then partitioned between ethyl acetate and water. The organicphase was dried over MgSO₄, filtered and evaporated to gave a pale brownsolid Chromatography on silica gel (eluent gradient—isohexane to CH₂Cl₂)gave tert-butyl (4,5-dichloro-2-formyl-3-thienyl)carbamate as a paleyellow solid. Yield 0.31 g (63%). ¹H NMR (300 MHz, CDCl₃) 10.01 (s, 1H),6.83 (br s, 1H), 1.52 (s, 9H); ESP⁻ 294.07

The product from step 4 (300 mg) was dissolved in dry DMF (2 ml) underan argon atmosphere, and KHCO₃ (102 mg) was added followed by methylbromoacetate (96 μl). The mixture was then heated to 60° C., for 3½hours. After stirring overnight at room temperature, further KHCO₃ (51mg) and methyl bromoacetate (48 μl) were added and the mixture heated at60° C. for a further 1 hour 30 minutes.

The reaction mixture was then partitioned between ethylacetate and H₂O.The organic layer was dried over MgSO₄, filtered and evaporated to aclear, orange oil. Chromatography on silica gel (eluentgradient—isohexane to CH₂Cl₂ then to Et₂O) gave methylN-(tert-butoxycarbonyl)-N-(4,5-dichloro-2-formyl-3-thienyl)glycinate asa clear yellow oil (0.42 g). ¹H NMR (300 MHz, CDCl₃) (exists as 2:1mixture of rotamers) 10.13 (s, 1H), 4.78 (d, 1H), 3.87 (d, 1H), 3.72 (s,3H), 1.38 (s, 9H) (major rotamer); 10.05 (s, 1H), 4.58 (d, 1H), 3.87 (d,1H), 3.75 (s, 3H), 1.50 (s, 9H) (minor rotamer)

Under an argon atmosphere, the product of step 5 (746 mg) was dissolvedin acetic acid (5 ml) and acetic anhydride (0.41 ml) added. Afterheating for 21 hours at 120° C., the reaction mixture was evaporatedunder reduced pressure, and the residue partitioned between CH₂Cl₂ andaqueous sodium bicarbonate solution. The organic layer was dried overMgSO₄, filtered and evaporated under reduced pressure.

The organic layer was dried over MgSO₄, filtered and evaporated underreduced pressure. Chromatography on silica gel (eluentgradient—isohexane to CH₂Cl₂ then to Et₂O: CH₂Cl₂ (3:97)) gave themethyl N-acetyl-N-(4,5-dichloro-2-formyl-3-thienyl)glycinate as a clearyellow oil (34 mg). ¹H NMR (300 MHz, CDCl₃) 10.22 (s, 1H), 5.00 (d, 1H),3.75 (d, 1H), 3.72 (s, 3H), 1.99 (s, 3H)

The product of step 6 (103 mg) under an argon atmosphere and K₂CO₃ (70mg) were mixed together and dry DMF (1 ml) added. The suspension quicklywent red. After 2 hrs at room temperature, the temperature was raised to60° C. for 165 minutes. The reaction mixture was cooled to roomtemperature and stirred overnight.

The product was then worked-up using procedures as described in step 6,and the organic phase dried over Na₂SO₄. Chromatography on silica gel(eluent gradient—isohexane to CH₂Cl₂ then to Et₂O) gave methyl2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylate as a white solid (37mg)(45%). ¹H NMR (300 MHz, d⁶-DMSO) 12.86 (br s, 1H), 7.20 (s, 1H), 3.86(s, 3H); ESP⁻ 248.04

The ester from step 7 (1.03 g) was suspended in methanol (7.5 ml) andheated to 60° C. A solution of LiOH (346 mg, 2 eq) in H₂O was addeddropwise giving an orange suspension. After complete addition, thesuspension was heated to reflux for 1 hour, whereupon it had become aclear orange solution. The reaction mixture was concentrated to almostdryness under reduced pressure, then acidified with 2M aqueoushydrochoric acid, and extracted with ethyl acetate (twice). The ethylacetate layer was dried over MgSO₄, filtered and evaporated underreduced pressure. Residual traces of MeOH were removed by azeotropingwith toluene to leave the desired2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid as an off whitesolid (0.98 g, 100%).

¹H NMR (400 MHz, d⁶-DMSO) 12.79 (or s, 1H), 12.63 (br s, 1H), 7.09 (s,1H), 3.86; ESP⁻ 234.21

1. A process for preparing a compound of formula (I)

where R⁴ and R⁵ are independently selected from halo; and R⁶ is hydrogenor a protecting group, which process comprises cyclisation of a compoundof formula (II)

where R⁴, R⁵ and R⁶ are as defined in relation to formula (I), and R⁷ isa nitrogen protecting group; and removing the group R⁷; and thereafteroptionally removing any protecting group R⁶.
 2. A process according toclaim 1 wherein R⁷ is a group of sub-formula (i)

where R⁸ is a straight chain alkyl group of from 1 to 6 carbon atoms. 3.A process according to claim 1, for preparing a compound of formula (I)where R⁶ is hydrogen, wherein the method further comprises the step ofreacting the compound of formula (I) obtained with an amine of formula(XIII)

where R¹⁴ is selected from hydrogen or C₁₋₈alkyl, m is an integer offrom 0 to 4, each R¹⁵ is the same or different and is selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino, C₃₋₈cycloalkyl,C₃₋₈cycloalkylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic group and(heterocyclic group)C₁₋₆alkyl; wherein R¹⁵ may be optionally substitutedon carbon by one or more groups selected from P and wherein if saidheterocyclic group contains an —NH— moiety that nitrogen may beoptionally substituted by a group selected from R; each R¹⁶ is the sameor different and is selected from is hydrogen or C₁₋₆alkyl; R¹⁷ isselected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl,difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl,N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0to 2, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl, sulphamoylamino,N-(C₁₋₆alkyl)sulphamoylamino, N,N-(C₁₋₆alkyl)₂sulphamoylamino,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonylaminocarbonyl,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino and a group -E-F-G-H; wherein Eand G are independently selected from a direct bond, —O—, —S—, —SO—,—SO₂—, —OC(O)—, —C(O)O—, —C(O)—, —NR^(a)—, —N^(a)C(O)—, C(O)NR^(a)—,—SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)C(O)NR^(b)—, —OC(O)NR^(a)—,—NR^(a)C(O)O—, —NR^(a)SO₂NR^(b)—, —SO₂NR^(a)C(O)— and —C(O)NR^(a)SO₂—;wherein R^(a) and R^(b) are independently selected from hydrogen orC₁₋₆alkyl which is optionally substituted by a group V; F isC₁₋₆alkylene optionally substituted by one or more Q or a direct bond; His selected from aryl, C₃₋₈cycloalkyl and heterocyclic groups; wherein Hmay be optionally substituted on carbon by one or more groups selectedfrom S and wherein if said heterocyclic group contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from T;P, S and Q are independently selected from halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, N-(C₁₋₆alkyl)-N-(C₁₋₆alkoxy)carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino, C₃₋₈cycloalkyl, aryl andheterocyclic group; wherein P, S and Q may be optionally andindependently substituted on carbon by one or more groups selected fromV and wherein if said heterocyclic group contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from U; V isselected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl,N-benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl; R, T and U areindependently selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl,C₁₋₄alkoxycarbonyl, carbamoyl, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)carbamoyl, phenyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl wherein R, T and U may be optionally and independentlysubstituted on carbon by one or more groups selected from V; producing acompound of formula (XIV)

where R⁴, R⁵, R¹⁵, R¹⁶, R¹⁷ and m are as defined above, or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof.